April 19, 2011

Hallmarks of cancer v. 2.0

In 2000, Douglas Hanahan and Robert Weinberg initially proposed six hallmarks of cancer that form an organizing principle for understanding the remarkable diversity of "cancer." Their update, "Hallmarks of Cancer: The Next Generation," was published in the March 4, 2011 issue of Cell.

The six hallmarks of cancer are distinctive and complementary capabilities enabling tumor growth and metastatic dissemination and are a solid foundation for understanding the biology of cancer . These six hallmark capabilities of cancer, as originally defined, include the ability to sustain chronic proliferation, the ability to evade growth suppressors, the ability to resist cell death, the ability to achieve replicative immortalization, the ability to induce angiogenesis, and, finally, the ability to activate mechanisms for invasion and metastasis. These characteristics, common to all types of cancer, form a fundamental an understanding of the biology of cancer.

The authors use this review article, however, to update the massive progress that is been made in the last decade from their original article. They identify to enabling characteristics that allow cancer cells to acquire these functional capabilities. The most common is the development of genomic instability in cancer cells. This not only generates random mutations including chromosomal rearrangements but also rare genetic changes that can drive some of these hallmark capabilities. A second enabling characteristic involves the inflammatory state of premalignant and frankly malignant lesions which serve to promote tumor progression through various mechanisms.

The authors highlight other distinct attributes of cancer cells which have been proposed as also being functionally important for the development of cancer and may also be added to the list of core hallmarks. Two are especially compelling. The first involves the major reprogramming of cellular energy metabolism in order to support continuous cell growth and proliferation. The second involves active evasion by cancer cells from attack and elimination by immune cells. This latter capability highlights the dichotomous role of the immune system which can both antagonize and enhanced tumor development and progression.

The authors also include a very nice summary of the advances made in our understanding of the tumor microenvironment. They enumerate the various cell types that are known to contribute to the biology of the tumor microenvironment and also discuss some of the regulatory signaling that controls their individual and collective functions. Also included in their discussion is recent research showing the connections between the acquisition of cancer stem-like cells and the epithelial-mesenchymal transition differentiation program.

One interesting topic they discuss is the role of pericytes which is a cell type that I haven't thought of as being an important part of the tumor microenvironment. Pericytes represent a very specialized mesenchymal cell type that have fingerlike projections that wrap around the endothelial tubing of blood vessels. In normal cells or normal tissues, pericytes are known to provide paracrine support signals to the normally quiesent endothelium. The authors discuss research in which genetic and pharmacological disruption of the recruitment and association of pericytes which has demonstrated the functional importance of the cells in supporting the tumor endothelium. The authors conclude with a brief summary of possible therapeutic targeting of the hallmarks of cancer. They propose drugs that could interfere with each of the acquired capabilities necessary for tumor growth and progression and summarize some of which are involved in clinical trials or in some cases approved for clinical use in treating certain forms of cancer.

This is a long review article (hence the long post!) but well worth your effort and it is the most up-to-date and accessible review of our current understanding of the biology of cancer.